Composition comprising (-)-delta9-trans-tetrahydrocannabinol

ABSTRACT

A composition comprising a tetrahydrocannabinol compound, a solvent and an acid, wherein the tetrahydrocannabinol compound may be Δ 8  tetrahydrocannabinol, (−)-Δ 9 -trans-tetrahydrocannabinol or a side chain alkyl derivative of either compound, the solvent may be an oil or C 1 -C 4  alcohol (e.g. sesame oil or ethanol), and the acid may be an organic acid or a mineral acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.11/595,682, filed Nov. 10, 2006, the disclosure of which is incorporatedherein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to a composition comprising(−)-Δ⁹-trans-tetrahydrocannabinol or related compounds.

BACKGROUND OF THE INVENTION

The compound (−)-Δ⁹-trans-tetrahydrocannabinol is the active ingredientin marijuana. It is used therapeutically as an inhalant or an oral drugfor stimulation of appetite among AIDS and cancer chemotherapy patients.Tetrahydrocannabinols (THCs) can be isolated from marijuana (a mixtureof leaves and flowering heads of the plant Cannabis Sativa).Alternatively, THCs can be obtained by synthetic routes, e.g. asdescribed in WO 02/096899.

Pure (−)-Δ⁹-trans-tetrahydrocannabinol that has been producedsynthetically and purified is unstable and is liable to degrade toproducts such as cannabinol (which is inactive) andΔ⁸-tetrahydrocannabinol (which is less potent). AlthoughΔ⁸-tetrahydrocannabinol has similar activity to as(−)-Δ⁹-trans-tetrahydrocannabinol it is only approx. 75% as potent andalso tends to degrade to other compounds including cannabinol.Dissolving the (−)-Δ⁹-trans-tetrahydrocannabinol in a solvent or carrierimproves the stability, but it is still usual to store the solutionsunder refrigerated conditions, e.g. at 5° C., to prevent degradation.The present inventors have sought to improve the stability of solutionsof (−)-Δ⁹-trans-tetrahydrocannabinol and Δ⁸-tetrahydrocannabinol.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a composition comprising:

-   -   (a) a tetrahydrocannabinol compound chosen from Δ⁸        tetrahydrocannabinol, (−)-Δ⁹-trans-tetrahydrocannabinol and side        chain alkyl derivatives of either compound,    -   (b) a solvent chosen from oils and C₁-C₄ alcohols, and    -   (c) an acid.

By side chain alkyl derivatives of either compound we mean compoundswith the structure of either of the compounds depicted in the FIGURE, inwhich R represents an alkyl side chain. Of particular interest, arecompounds in which R is 1,1 dimethylheptyl.

BRIEF DESCRIPTION OF THE DRAWINGS

The FIGURE shows the chemical structures for alkyl substituted(−)-Δ⁸-trans-tetrahydrocannabinol derivatives and(−)-Δ⁹-trans-tetrahydrocannabinol derivatives.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have found that the addition of the acid improves thestability of the composition, i.e. there is less degradation of thetetrahydrocannabinol compound during prolonged storage of thecomposition.

The composition includes a solvent. The solvent may be chosen from oilsand C₁-C₄ alcohols. Suitable examples of oils include sesame oil, oliveoil, canola oil and combinations thereof. Suitable examples of C₁-C₄alcohols include methanol, ethanol, propanol, iso-propanol and butanol.

According to one embodiment, the solvent is sesame oil. The sesame oilmay be refined or unrefined, but is preferably refined (the US Food andDrug Administration standards require that refined sesame oil is used inpharmaceutical products). The composition may further comprise othersolvents, but preferably comprises only sesame oil as the solvent.According to an alternative embodiment, the solvent is ethanol.

The acid used in the composition may be an organic acid. When an organicacid is used, the organic acid is suitably chosen from citric acid,ascorbic acid, malic acid, oxalic acid, succinic acid and tartaric acid,and is preferably citric acid.

The acid used in the composition may be a mineral acid. When a mineralacid is used, the mineral acid is suitably chosen from phosphoric acid,hydrochloric acid, nitric acid and sulphuric acid, and is preferablyphosphoric acid.

Weak acids have an especially positive stabilizing effect on(−)-Δ⁹-trans-tetrahydrocannabinol and its derivatives, forming astabilized composition. If the amount or concentration of strong acid istoo large, the Δ⁹-isomer degrades to the Δ⁸-isomer.

The acid may be added to the other constituents either as a separatecomponent, or the acid may be formed in a solution of the otherconstituents. An example of the latter is the use of dissolved CO₂ inethanol, which also stabilizes the Δ⁹-isomer, probably due to formationof carbonic acid.

The amount of acid is suitably from 0.01-2% as a weight percentage ofthe composition, preferably from 0.02-1% and most preferably from0.05-0.5%.

The amount of (−)-Δ⁹-trans-tetrahydrocannabinol in the composition issuitably from 0.1-15% as a weight percentage of the composition,preferably from 1 to 10%.

The composition may further comprise antimicrobial agents such as methylparaben or propyl paraben. The composition may further comprisepreservatives such as alpha-tocopherol or butylated hydroxytoluene(BHT). The composition may further comprise antioxidants. Theantimicrobial agents, preservatives and antioxidants may be used aloneor in combination.

In a preferred embodiment, the composition of the invention consistsessentially of a tetrahydrocannabinol compound, an oil or a C₁-C₄alcohol, and 0.01-2 wt % of an acid chosen from the group consisting ofcitric acid, ascorbic acid, malic acid, oxalic acid, succinic acid,tartaric acid, phosphoric acid, hydrochloric acid, nitric acid andsulphuric acid. Additional components (e.g. antimicrobial agents,preservatives, antioxidants) may comprise up to 1 wt % of the solution.In an especially preferred embodiment, the composition of the inventionconsists essentially of (−)-Δ⁹-trans-tetrahydrocannabinol, sesame oiland 0.05-0.5 wt % citric acid or phosphoric acid, wherein additionalcomponents may comprise up to 1 wt % of the solution.

Compositions according to the invention may be prepared by adding theacid to a solution of a tetrahydrocannabinol compound in sesame oil or aC₁-C₄ alcohol and mixing. Solutions of (−)-Δ⁹-trans-tetrahydrocannabinolin sesame oil may be prepared by dissolving pure(−)-Δ⁹-trans-tetrahydrocannabinol in sesame oil, or by mixing sesame oilwith a solution of (−)-Δ⁹-trans-tetrahydrocannabinol in ethanol, andthen distilling off the ethanol.

The following examples are illustrative but not limiting of theinvention.

Composition Preparation: Sesame Oil Solvent

Sesame oil was degassed under vacuum distillation and blanketed withnitrogen. The sesame oil was refined sesame oil from Jeen International(Compositions 1-2, 7-17) or Dipasa (Compositions 3-6). A solution of(−)-Δ⁹-trans-tetrahydrocannabinol in ethanol was added to the sesame oiland the acid was also added. The solution was mixed and the ethanol wasremoved using a rotary evaporator.

Each composition contained 6.65 wt % (−)-Δ⁹-trans-tetrahydrocannabinolbased on the weight of the composition. The additional components ineach composition were as shown in Table 1 below:

TABLE 1 Compositions 1-18 in Sesame Oil Solvent Acid Other componentsComposition 1 None None Composition 2 0.1 wt % citric acid NoneComposition 3 None None Composition 4 0.1 wt % citric acid NoneComposition 5 None Methyl paraben, Propyl paraben, Alpha tocopherol, BHTComposition 6 0.1 wt % citric acid Methyl paraben, Propyl paraben, Alphatocopherol, BHT Composition 7 None None Composition 8 0.1 wt % ascorbicacid None Composition 9 0.1 wt % acetic acid None Composition 10 0.1 wt% citric acid None Composition 11 0.1 wt % lactic acid None Composition12 0.1 wt % fumaric acid None Composition 13 0.1 wt % malic acid NoneComposition 14 0.1 wt % oxalic acid None Composition 15 0.1 wt %succinic acid None Composition 16 0.1 wt % salicylic acid NoneComposition 17 0.1 wt % tartaric acid None Composition 18 0.1 wt %phosphoric acid None

Composition Preparation: Ethanol Solvent

Citric acid was added to 2 ml samples of a solution of(−)-Δ⁹-trans-tetrahydrocannabinol in ethanol (the concentration of the(−)-Δ⁹-trans-tetrahydrocannabinol was 66.6 mg/ml). The solutions weremixed. The amount of citric acid in each solution is shown in Table 2below:

TABLE 2 Compositions 19-24 in Ethanol Solvent Weight % of citric acidcompared to the weight Amount of citric acid (mg) of Δ⁹-THC Composition19 0.00 0.0% Composition 20 2.51 1.9% Composition 21 2.01 1.5%Composition 22 0.50 0.4% Composition 23 0.25 0.2% Composition 24 0.130.09% 

Stability: Sesame Oil Solvent

The stability of the sesame oil compositions (compositions 1-18) wasassessed at three different conditions: 5° C. or Normal Storage(Refrigerated) Conditions; 25° C./60% Relative Humidity or AcceleratedConditions; and 40° C./75% Relative Humidity or High Temperature/HighHumidity Conditions. The degradation of the(−)-Δ⁹-trans-tetrahydrocannabinol was monitored using a High PerformanceLiquid Chromatography (HPLC) method with ultraviolet detection at 228nm. Each detected impurity peak was measured using percent peak area (%PA) with respect to the peak area counts for(−)-Δ⁹-trans-tetrahydrocannabinol for each chromatogram. Each impuritypeak was identified with a relative retention time (RRT) relative to the(−)-Δ⁹-trans-tetrahydrocannabinol peak elution time from eachchromatogram. Impurity peaks measuring above 0.05% PA were recorded.

The impurities that are attributed to the degradation of(−)-Δ⁹-trans-tetrahydrocannabinol elute from the HPLC column at a RRTwindow of 0.56 to 0.95 and at a RRT of 1.06. The impurities cannabinoland Δ⁸-tetrahydrocannabinol elute from the column at RRTs of 0.95 and1.06 respectively.

Table 3 shows the results of the stability tests for compositions 1-18.The period of time after which the degradation of the composition wasassessed is indicated beside each table.

TABLE 3 Stability tests for compositions 1-18 % Peak Areas according toRelative Retention Time (RRT) Condition 0.56 0.57 0.58 0.61 0.63 0.660.67 0.70 0.74 0.78 0.90 0.95 1.06 Composition 1, 1 month Initial 0.2825° C./60% RH 4.13 4.45 0.96 3.11 10.2 2.35 0.22 0.36 1.46 4.06 5.33 40°C./75% RH 8.09 5.35 2.43 4.91 0.29 15.62 0.28 0.49 1.86 2.99 Composition2, 3 months Initial  5° C. 0.08 0.05 0.05 25° C./60% RH 0.18 0.13 0.070.07 0.16 0.37 0.29 40° C./75% RH 1.96 0.22 0.91 0.17 0.45 0.36 0.3 0.051.25 4.16 2.17 Composition 3, 3 months Initial 0.12  5° C. 0.29 0.510.29 0.13 3.96 0.22 0.35 1.89 0.15 0.08 25° C./60% RH 0.85 0.74 1.971.23 0.72 6.13 1.81 0.06 0.23 2.55 0.44 2.03 0.64 40° C./75% RH 0.160.52 0.31 0.65 0.74 3.72 0.45 0.02 0.08 1.02 1.96 1.46 0.7 Composition4, 3 months Initial  5° C. 0.05 25° C./60% RH 0.19 0.10 0.10 0.20 0.1440° C./75% RH 1.96 0.15 0.53 0.29 0.30 0.17 1.11 2.62 0.41 Composition5, 3 months Initial 1.54  5° C. 0.05 0.12 0.08 0.06 1.36 0.05 0.09 0.3025° C./60% RH 0.40 0.65 0.2 0.13 0.41 0.50 0.37 0.14 0.92 0.12 0.27 0.481.00 40° C./75% RH 1.05 0.63 0.23 0.11 0.91 0.62 0.22 1.07 0.11 0.541.63 1.74 Composition 6, 3 months Initial 0.05 1.54 RF 5° C. 0.06 1.520.11 0.05 25° C./60% RH 0.09 0.06 0.07 1.52 0.53 0.3 40° C./75% RH 0.970.21 0.15 0.52 0.25 0.32 0.2 0.18 1.57 0.63 2.96 1.96 Composition 7, 4weeks Initial 0.03 0.03 0.02 0.01 0.02  5° C. 0.01 0.11 0.02 0.04 0.040.01 0.05 25° C./60% RH 0.19 0.16 0.13 0.11 1.76 0.51 0.22 0.01 0.050.05 40° C./75% RH 0.23 0.21 0.46 1.41 0.67 5.60 0.22 0.07 1.00 0.810.29 0.56 0.05 Composition 8, 4 weeks Initial 0.01 0.01 0.01 0.01 0.02 5° C. 0.02 0.01 0.02 25° C./60% RH 0.03 0.03 0.02 0.01 0.02 40° C./75%RH 0.02 0.01 0.06 0.11 0.03 0.02 0.02 0.04 0.05 0.06 Composition 9, 4weeks Initial 0.02 0.04 0.03 0.02  5° C. 0.17 0.10 0.02 0.1 0.02 0.670.16 0.15 0.15 0.02 0.05 25° C./60% RH 0.13 0.23 0.36 1.00 0.09 3.180.46 0.02 0.58 0.59 0.1 0.68 0.14 40° C./75% RH 0.65 1.25 0.29 2.95 0.322.99 1.71 0.04 0.30 0.12 0.49 3.69 0.7 Composition 10, 4 weeks Initial0.02 0.01 0.01 0.02  5° C. 0.01 0.01 25° C./60% RH 0.04 0.03 0.01 0.0240° C./75% RH 0.11 0.11 0.02 0.02 0.02 0.02 0.03 0.16 0.12 0.14Composition 11, 4 weeks Initial 0.02 0.02  5° C. 0.02 0.01 0.02 0.020.03 25° C./60% RH 0.02 0.01 0.09 0.01 0.04 0.11 0.07 40° C./75% RH 0.020.19 0.12 0.27 0.04 0.16 0.04 0.02 0.33 0.60 0.43 Composition 12, 4weeks Initial 0.02 0.01 0.02 0.03 0.01  5° C. 0.26 0.10 0.09 0.05 0.420.17 0.09 0.12 0.01 0.02 0.06 25° C./60% RH 0.08 0.09 0.12 0.02 0.070.38 0.1 0.02 0.04 0.07 0.19 0.19 0.67 40° C./75% RH 0.42 0.11 0.53 0.070.16 0.31 0.32 0.07 0.04 0.98 1.41 2.58 Composition 13, 4 weeks Initial0.02  5° C. 0.01 0.01 25° C./60% RH 0.01 0.02 0.02 0.03 0.03 40° C./75%RH 0.15 0.02 0.06 0.04 0.03 0.03 0.15 0.18 0.18 Composition 14, 4 weeksInitial 0.01 0.02  5° C. 0.05 0.01 0.02 25° C./60% RH 0.16 0.03 0.030.02 40° C./75% RH 0.04 0.03 0.35 0.02 0.11 0.12 0.02 Composition 15, 4weeks Initial 0.02 0.02 0.01 0.02  5° C. 0.01 0.01 0.02 25° C./60% RH0.03 0.02 0.01 0.03 40° C./75% RH 0.05 0.01 0.25 0.03 0.08 0.08 0.030.03 0.11 0.10 0.28 Composition 16, 4 weeks Initial 0.01 0.04 0.01 0.010.02 0.01 0.03  5° C. 0.01 0.16 0.03 0.08 0.04 0.05 0.15 0.01 0.22 0.0725° C./60% RH 0.36 0.1 1.87 0.58 0.63 0.75 0.01 0.19 2.76 0.05 4.27 0.1540° C./75% RH 0.41 0.27 0.99 0.17 0.45 0.34 0.77 0.05 0.08 2.97 0.64 4.50.59 Composition 17, 4 weeks Initial 0.02 0.01 0.02 0.02  5° C. 0.010.02 25° C./60% RH 0.02 0.02 0.02 0.02 40° C./75% RH 0.13 0.04 0.04 0.010.04 0.03 0.12 0.12 0.17 Composition 18, 16 days Initial 1.58 0.26 0.550.36 0.05 25° C./60% RH 3.39 0.20 0.17* 0.09 0.09 1.08 40° C./75% RH3.39 0.20 0.18* 0.08 0.10 1.08 data after 1 week, not 16 days

Compositions 1, 3, 5 and 7 did not contain any organic acid, and thetables show that considerable degradation occurred during theobservation period. By contrast, the degradation observed forcompositions 2, 4 and 6 (which all contained 0.1 wt % citric acid) wasconsiderably less. Compositions 5 and 6 both contained antimicrobialagents and preservatives, yet composition 6 (containing 0.1 wt % citricacid) was more stable than composition 5.

Compositions 8-18 contained a variety of acids. Compositions 8, 10, 11,12, 13, 14, 15, 17 and 18 (containing 0.1 wt % ascorbic acid, 0.1 wt %citric acid, 0.1 wt % lactic acid, 0.1 wt % fumaric acid, 0.1 wt % malicacid, 0.1 wt % oxalic acid, 0.1 wt % succinic acid, 0.1 wt % tartaricacid and 0.1 wt % phosphoric acid respectively) all showed improvedstability compared to composition 7 (containing no organic acid).Compositions 9 and 16 (containing 0.1 wt % acetic acid and 0.1 wt %salicylic acid) did not show an appreciable improvement compared tocomposition 7 and it would seem that these acids are less effective atimproving stability (although the inventors believe that these acid mayprovide an improvement if used at another concentration).

Stability: Ethanol Solvent

The stability of the ethanol compositions (compositions 19-24) wasassessed in substantially the same manner as for the sesame oilcompositions except that they were only assessed at only one set ofconditions (40° C.) and the compositions were analysed after 60 hoursand 1 month.

Table 4 shows that the composition that did not contain citric acid(composition 19) showed the greatest degradation and there seems to be aslight correlation between increasing citric acid content and increasedstability.

TABLE 4 Stability tests for compositions 19-24 % Peak Areas according toRelative Retention Time (RRT) Condition 0.57 0.58 0.59 0.61 0.63 0.660.67 0.70 0.74 0.78 0.82 0.90 0.95 Initial 0.11 Composition 40° C./60 hr0.04 0.04 0.25 0.02 1.80 0.35 0.02 19 40° C./1 mo 0.34 0.34 0.14 8.61.58 5.13 0.13 2.33 0.07 1.46 0.52 0.34 Composition 40° C./60 hr 0.30.02 0.04 0.07 20 40° C./1 mo 0.02 2.38 0.19 0.03 0.06 0.02 0.05 0.010.58 Composition 40° C./60 hr 0.04 0.3 0.02 0.01 0.05 0.08 21 40° C./1mo 0.02 2.51 0.2 0.02 0.06 0.02 0.05 0.01 0.6 Composition 40° C./60 hr0.35 0.03 0.07 0.11 0.04 22 40° C./1 mo 0.02 3.37 0.27 0.06 0.06 0.030.23 0.02 0.69 Composition 40° C./60 hr 0.31 0.03 0.11 0.11 0.02 23 40°C./1 mo 0.02 0.02 3.03 0.25 0.12 0.04 0.03 0.42 0.01 0.51 Composition40° C./60 hr 0.02 0.28 0.03 0.16 0.02 0.11 0.02 24 40° C./1 mo 0.02 1.710.14 0.13 0.02 0.03 0.39 0.24

1. A composition comprising: (a) (−)-Δ⁹-trans-tetrahydrocannabinol, (b)a solvent comprising sesame oil, and (c) an acid selected from the groupconsisting of acetic acid, lactic acid, oxalic acid, succinic acid,salicylic acid and tartaric acid, and wherein after up to 4 weeks at (i)5° C., (ii) 25° C./60% relative humidity, or (iii) 40° C./75% relativehumidity, the composition comprises: a′) ≦3.69% cannabinol when the acidis acetic acid; b′) ≦0.60% cannabinol when the acid is lactic acid; c′)≦0.12% cannabinol when the acid is oxalic acid; d′) ≦0.1% cannabinolwhen the acid is succinic acid; e′) ≦4.5% cannabinol when the acid issalicylic acid; or f′) ≦0.12% cannabinol when the acid is tartaric acid.2. A composition comprising: (a) (−)-Δ⁹-trans-tetrahydrocannabinol, (b)a solvent comprising sesame oil, and (c) phosphoric acid, and whereinthe composition comprises ≦1.08% cannabinol after up to 16 days at (i)25° C./60% relative humidity, or (ii) 40° C./75% relative humidity.
 3. Acomposition consisting essentially of: a)(−)-Δ⁹-trans-tetrahydrocannabinol, b) a solvent comprising sesame oil,and c) an acid selected from the group consisting of ascorbic acid,malic acid and fumaric acid, and, optionally, one or more anti-oxidants,antimicrobial agents, preservatives or a combination thereof, andwherein after up to 4 weeks at (i) 5° C., (ii) 25° C./60% relativehumidity, or (iii) 40° C./75% relative humidity, the compositioncomprises: a′) ≦0.05% cannabinol when the acid is ascorbic acid; b′)≦1.41% cannabinol when the acid is fumaric acid; or c′) ≦0.18%cannabinol when the acid is malic acid.
 4. A composition comprising: (a)a tetrahydrocannabinol compound selected from Δ⁸ tetrahydrocannabinol,(−)-Δ⁹-trans-tetrahydrocannabinol and side chain alkyl derivatives ofeither compound, (b) a solvent comprising C₁-C₄ alcohols, and (c) anacid selected from the group consisting of ascorbic acid, malic acid andfumaric acid.
 5. A composition comprising: (a) a tetrahydrocannabinolcompound selected from Δ⁸ tetrahydrocannabinol,(−)-Δ⁹-trans-tetrahydrocannabinol and side chain alkyl derivatives ofeither compound, (b) a solvent comprising ethanol, and (c) carbonic acidformed from dissolved CO₂ in the ethanol.
 6. A composition consistingessentially of: a) a tetrahydrocannabinol compound selected fromΔ⁸-tetrahydrocannabinol, (−)-Δ⁹-trans-tetrahydrocannabinol and sidechain alkyl derivatives of either compound, b) a solvent comprisingethanol, and c) carbonic acid formed from dissolved CO₂ in the ethanol,and, optionally, one or more anti-oxidants, antimicrobial agents,preservatives or a combination thereof.